Novel trifluoromethyl derivatives of substituted diols



United States Patent 3,134,319 NOVEL TRTFLUOROMETHYL DERIVATEVES @F SUBSTITUTED DIOLS Maxweli Gordon, Elkins Park, and Erwin J. Pachter, Erdenheirn, Pa., assignors to Smith Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Fiied Nov. 14, 1966, Ser. No. 68,647 7 Claims. ((1 260-618) This invention relates to novel organic compounds and more specifically to certain vic-diols embracing the trifiuoromethyl group and possessing valuable pharmacological properties.

The compounds of our invention may be represented by the following general formula:

wherein X is a member selected from the group consisting of CF3-, CF30-, CF3S, and and R, R and R" are selected from the group consisting of hydrogen, lower alkyl of from 1 to 3 carbon atoms, and phenyl, R, R, R being the same only when representing lower alkyl.

The compounds of this invention possess anticonvulsive and mild tranquilizing properties. The compounds can be advantageously administered orally in any of the known pharmaceutical forms and demonstrate few if any untoward side effects.

The compounds of this invention are prepared by reacting an appropriate vic-hydroxy ketone with a Grignard reagent of the formula:

The conditions employed are analogous to those known and employed in the art for similar Grignard reactions of this type.

The preferred compounds of our invention are those wherein R, R and R" represent methyl and X represents CF The following examples will further serve to typify the mode of our invention, but should not be construed as limiting the scope thereof, the scope being defined by the appended claims.

Example 1 To 113 g. of p-trifiuoromethylphenyl bromide in 1 l. of anhydrous ether is added 12.5 g. of magnesium turnings. When formation of this Grignard reagent is complete, a solution of 21 g. of 2-methyl-2-hydroxy-3-butanone in 50 ml. of anhydrous ether is added dropwise at such a rate so as to maintain a slow reflux. At the end of this time, the mixture is stirred for hours and to it is added 100 ml. of saturated aqueous ammonium chloride solution, followed by an additional 100 ml. of 2 N hydrochloric acid. The mixture is stirred for 30 minutes, the layers then separated and the ethereal layer next evaporated to dryness. The residue is recrystallized from cyclohexane, clarified with charcoal and again recrystallized from cyclohexane to yield 2- (p-trifluoromethylphenyl)-3- methyl-2,3-butanediol, M.P. 9899.

Similarly by employing 122 g. of p-trifluoromethoxyphenyl bromide in place of p-trifluoromethylphenyl bromide, there is formed the corresponding Grignard reagent p-trifluoromethoxyphenyl magnesium bromide which when reacted with 2-methyl-2-hydroxy-3-butanone accord- 3,134,819 Patented May 26, 1.964

ing to the above procedure yields 2-(p-trifluoromethoxyphenyl -3 -methyl-2,3 -butanediol.

Likewise, p-trifiuoromethylthiophenyl bromide and ptrifiuoromethylsulfonylphenyl bromide are employed in preparation of the corresponding Grignard reagent and these in turn reacted with 2-methyl-2-hydroxy-3-butanone to yield respectively 2-(p-trifiuoromethylthiophenyl)-3- methyl-2,3-butanediol and 2-(p-trifiuoromethylsulfonylphenyl) -3 -methyl-2,3 -butanediol.

Example 2 An ethereal solution of p-triiluoromethylphenyl magnesium bromide is prepared in the manner of Example 1 and to it is added a solution of 24 g. of 3methyl-3-hydroxy-Z-pentanone in 50 ml. of ether in a dropwise manner so as to maintain a slow reflux. The mixture is then stirred for 10 hours and treated with ml. of saturated aqueous ammonium chloride solution followed by 100 ml. of saturated aqueous ammonium chloride solution followed by 100 ml. of 2 N hydrochloric acid. The mixture is stirred for an additional 30 minutes, the layers separated and the ethereal layer evaporated to dryness. The solid residue so obtained is recrystallized from cyclohexane, clarified with charcoal and again recrystallized from cyciohexane to yield 2-(p-triiluoromethylphenyl)- 3-methyl-2,3-pentanediol.

In a similar manner, equivalent quantities of the following compounds are subjected to the above procedure: l-hydroxy-Z-pentanone, 5-hydroxy-4-octanone, 4-ethyl-4- hydroxy-B-hexanone, 2,5-dimethyl-4-hydroxy-3-hexanone. There are thus obtained upon execution of the steps therein described the compounds 2-(p-trifluoromethylphenyl)- 1,2 pentanediol, 4-(p-trifluoromethylphenyl)-4,5-octanediol, 3 (p-trifluoromethylphenyl)-4-ethyl-3,4-hexanediol, and 2,5-dimethyl-3-(p-trifluoromethylphenyl)-3,4-hexanediol.

Example 3 To the Grignard reagent prepared in Example 1 is added 31.4 g. of acetylphenylcarbinol in a dropwise fashion so as to maintain a slow reflux. After stirring for 10 hours, 100 ml. of saturated aqueous ammonium solution and 100 ml. of 2 N hydrochloric acid are added. Stirring is continued for 30 minutes, after which time the layers are separated and the organic layer evaporated to dryness. The residue which is thus formed is recrystallized from cyclohexane to yield l-phenyl-Z-(p-trifluoromethyl phenyl 1 ,2-propanediol.

In a similar manner methylbenzoylcarbinol is substituted for acetylphenylcarbinol in the above procedure and there is thus obtained 1 -phenyl-1-(p-trifiuoromethylphenyl) -l ,Z-propanediol.

Likewise by employing equivalent amounts of dimethylbenzoylcarbinol, acetylphenylmethylcarbinol, and benzoin, there are respectively obtained upon execution of the above procedure the compounds l-phenyl-l-(p-trifiuoromethylphenyl) Z-methyl-l,Z-propanediol, 2-phenyl-3-(ptrifiuorornethylphenyl)-2,3-butanediol, and l-phenyl-Z-(ptrifluoromethylphenyl)-ethylene glycol.

Example 4 p-Trifluoromethylthiophenyl magnesium bromide (prepared from g. of p-trifluoromethylthiophenyl bromide and 12 g. of magnesium) is substituted for p-trifluoromethylphenyl magnesium bromide in the procedure of Example 2 and there is thus obtained the compound 2- (p trifluoromethylthiophenyl)-3-methyl-2,3-pentanediol.

Similarly, by employing p-trifiuoromethoxyphenyl bromide and preparing the corresponding Grignard reagent, there is obtained the use of this reagent in the procedure of Example 2, the compound 2-(p-trifluoromethoxyphenyl)-3-methyl-2,3-pentanediol.

Example 5 Example 6 p-Trifluoromethylthiophenyl bromide is converted to the corresponding Grignard reagent in the manner heretofore described and treated with acetylphenylmetli l carbinol in the manner of Example 3. Upon completion of the steps therein described, there is obtained the compound 2 phenyl-3-(p-trifiuoromethylthiophenyl)-2,3-butanediol.

Example 7 To 146 g. of p-trifluoromethylsulfonylphenyl bromide is added 12.5 g. of magnesium turnings in 1 l. of anhydrous ether. To this reagent is added 33.8 g. of dimethylbenzoylcarbinol in the manner of Example 3. Completion of the steps as therein described then yields the compound 1- phenyl 1 (p-trifiuoromethylsulfonylphenyl)-2-methyl-1, 2-propanediol.

Qt We claim: 1. Compounds of the formula:

on on it 1k wherein X is a member selected from the group consisting of CF CF S, CF O, and CF SO and R, R, and R" are members selected from the group consisting of hydrogen, lower alkyl and phenyl, R, R, and R" being the same only when representing lower alkyl.

2. Compound according to claim 1 wherein X is CF;,-- and R, R and R" are lower alkyl.

3. Compounds according to claim 1 wherein X is CF;., and R and R are lower alkyl and R is hydrogen.

4. 1 phenyl-2-(p-trifluoromethylphenyl)-1,2-pr0panediol.

5. 2- (p-trifluorornethylphenyl -3 -methyl-2, 3 -butanediol.

6. 2-phenyl-3-(p-trifluoromethylphenyl)2,3-butanediol.

7. 3-(p-trifiuoromethylphenyl)-4-ethyl-3,4-hexanediol.

Tarrant et al.: Journal Organic Chem, 24:238239, 1959 (2 pages). 

1. COMPOUNDS OF THE FORMULA: 